Respiratory Distress Syndrome, the most severe form of acute lung injury, has been found to occur more frequently in alcoholics. In fact, chronic alcohol use is not only associated with increased incidence of acute lung injury, but also increased mortality. Despite its importance, the exact mechanisms by which alcohol abuse renders the host susceptible to acute lung injury remain poorly defined. We have identified a cell surface sensor for alcohol in lung cells and believe that it mediates many of the detrimental effects of alcohol in lung. In view of its perceived importance, this project seeks to further characterize this 'alcohol receptor' and investigate its role in the development of acute lung injury in the setting of chronic alcohol exposure. The work proposed was prompted by novel observations showing that: 1) receptors members of the nicotinic acetylcholine receptor (nAChR) family mediate the effects of ethanol in lung fibroblasts and 2) that ethanol-induced oxidant stress (through oxidation of the extracellular cysteine/cystine redox potential) might directly activate nAChRs. These observations have important implications in vivo since we have shown that subjects with chronic alcohol abuse who are otherwise 'healthy' show evidence of oxidant stress as well as activation of lung tissue remodeling. Based on the above, we hypothesize that chronic ethanol exposure renders the host susceptible to acute lung injury by acting on nAChRs present on lung cells. Furthermore, we hypothesize that oxidant stress can amplify these events by activating nAChRs directly through actions on specific cysteine residues strategically located near the ligand binding site of the receptor; new preliminary data support this hypothesis. Ultimately, downstream signals triggered by nAChRs result in a cascade of events that render the host susceptible to acute lung injury. This hypothesis will be tested in specific aims designed to: 1) Characterize the role of nAChRs in mediating the effects of ethanol in lung cells, 2) Examine the mechanisms by which a specific form of oxidant stress influences ethanol-induced nAChR activation, and 3) Determine the role of nAChRs in mediating ethanol-induced susceptibility to acute lung injury in vivo. PUBLIC HEALTH RELEVANCE: Chronic ethanol use has been associated with increased susceptibility to acute lung injury, a condition that affects over 200,000 Americans and that is associated with ~40% mortality. This project will explore how ethanol exposure renders the host susceptible to this condition by examining the cellular mechanisms that mediate the effects of ethanol in lung cells and how this impacts lung injury and repair.